Caspofungin is a new member of echinocandin antifungal drugs, which was developed in the early 21st century and first marketed in the United States in February 2001. It has a novel acting mechanism, which kills the fungus by inhibiting the enzyme β-D-glucan synthase, thus disturbing the integrity of the fungal cell wall. Caspofungin has the advantages of broad antifungal activities, no cross resistance and low toxicity, and it can be used to treat systemic fungal infections, including various invasive candidiasis and aspergillosis. It is more effective than amphotericin B, especially toward common refractory candidiasis.
Caspofungin has been semi-synthesized from the biologically fermented intermediate pneumocandin B0 (PB0). Various synthetic methods for caspofungin have been extensively described in patents such as U.S. Pat. No. 5,552,521, U.S. Pat. No. 5,936,062, US20100168415, WO2002083713, WO2007057141, CN101648994, CN101792486, etc. All these methods involve the key intermediate of formula I′ with the thiol substituted aromatic compound (HS—Ar), e.g. thiophenol, as a leaving group.
Due to the regioselectivity in the replacement of thiol substituted aromatic compounds, multiple chromatography purifications were required to afford the pure intermediates and final product in the preparation of caspofungin, which led to low yield, high cost, complex operation, and the like. Thus, there is still a need to develop new preparation methods for caspofungin.